Neurodegeneration disorders afflict many in the aging population and are a major cause of dementia and motor disorders in the elderly population. Many of these diseases are genetic and the identification of the underlying molecular defects allows the discovery of gene products that result in neuronal loss when abnormally expressed. Our overall goal is to understand the molecular mechanisms underlying age-related neuronal degeneration by identifying and functionally characterizing molecules necessary for neuronal survival in the aging brain. To achieve this goal we will study two mouse mutant strains, the sex-linked semidominant mutation Hq, and a newly identified recessive mutation, sti. Mice from these mutant strains develop ataxia upon aging that is an apparent result of the loss of cerebellar neurons. We hypothesize that Hq and sti mutant mice may provide ideal mouse models for neurodegeneration studies. To establish the role of these mutations in neuronal loss, we will determine the temporal course of this cell loss and whether this cell death is apoptotic in nature. We will make a high resolution map of the Hq and sti region and begin looking at candidate genes for the mutations. These pilot studies will delineate the function of the Hq and sti genes in aging neurons and will provide a strong basis for subsequent gene identification studies. Such studies may provide a basis for development of new strategies to prevent the cascade of cellular events culminating in neurodegeneration.